Mechanistic studies on obesity-deteriorated glucose and lipid metabolisms

肥胖导致糖脂代谢恶化的机制研究

• 批准号: 8575022
• 负责人: Chi Bun Chan
• 金额: $ 4.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-02-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575022
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Ablation; Address; Animals; Biochemical; Biochemistry; Blood; Complex; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Energy Metabolism; Enhancers; Event; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Genetic; Glucose; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Hormonal; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Intracellular Accumulation of Lipids; Knockout Mice; Lead; Lipids; Lipolysis; Measures; Metabolic; Metabolic Diseases; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Physiological; Process; Protein Kinase Interaction; Proteins; Receptor Activation; Regulation; Reporting; Research; Role; Signal Transduction; Skeletal Muscle; Therapeutic; Tissues; blood glucose regulation; cytokine; design; fatty acid oxidation; feeding; glucose metabolism; improved; in vivo; in vivo Model; insight; insulin receptor tyrosine kinase; insulin sensitivity; insulin signaling; lipid metabolism; novel; oxidation; prevent; protein complex; public health relevance; research study; sensor

DESCRIPTION (provided by applicant): Obesity is associated with impaired controls of glucose and lipid metabolisms. However, the molecular events leading to these metabolic defects are not well understood. In particular, it has been long recognized that both insulin receptor (IR) activity and fatty acid oxidation are impeded in the muscle of obese subjects by an indefinite mechanism. Our preliminary data show that IR interacts with a novel GTPase phosphoinositide 3- kinase enhancer-A (PIKE-A) to fully activate its kinase activity during insulin stimulation. This interaction is a metabolically regulated process as less IR/PIKE-A complex is founded in the skeletal muscle of obese mice and lipid-stimulated myotubes. We also found that genetic ablation of PIKE resulted in augmented AMP- activated protein kinase (AMPK) activation and lipolysis in muscle, thus protected the animals from diet- induced obesity and diabetes. Moreover, we observed an enhanced association between PIKE-A and AMPK in the skeletal muscle of diet-induced obese mice. Therefore, the interaction between PIKE-A, IR and AMPK may represent a novel regulation on lipid oxidation and insulin sensitivity, which is ravaged in the obese muscle. As a part of our long term goal to reveal the molecular mechanisms leading to various obesity-related disorders, we set forth the following studies to delineate the role of IR/PIKE-A/AMPK interaction in obesity-induced muscular insulin resistance and defective lipid oxidation. In this project, we will (1) characterize the molecular and functionl details of IR, PIKE-A and AMPK associations; (2) determine the mechanisms that regulate the IR/PIKE-A and PIKE-A/AMPK complexes formation with a special focus on lipotoxicity and inflammatory cytokines; and (3) study the obesity-induced pathology in muscle-specific PIKE knockout mice to demonstrate the critical role of IR/PIKE-A/AMPK interplay in energy and glucose homeostasis. Taken together, our proposed studies will provide a new mechanism to explain the alteration of insulin signaling and lipid metabolism in obese tissues, which is helpful to advance our understanding on the pathophysiology of obesity and improve the therapeutic design for its complications.

描述（由申请人提供）：肥胖与葡萄糖和脂质代谢控制受损相关。然而，导致这些代谢缺陷的分子事件还没有得到很好的理解。特别地，长期以来已经认识到胰岛素受体（IR）活性和脂肪酸氧化在肥胖受试者的肌肉中通过不确定的机制被阻碍。我们的初步数据表明，IR与一种新的GTT磷酸肌醇3-激酶增强子-A（PIKE-A）相互作用，在胰岛素治疗过程中完全激活其激酶活性。 刺激.这种相互作用是一种代谢调节过程，因为在肥胖小鼠的骨骼肌和脂质刺激的肌管中发现较少的IR/PIKE-A复合物。我们还发现，基因切除PIKE导致肌肉中AMP活化蛋白激酶（AMPK）活化和脂解增强，从而保护动物免于饮食诱导的肥胖和糖尿病。此外，我们观察到饮食诱导肥胖小鼠骨骼肌中PIKE-A和AMPK之间的关联增强。因此，PIKE-A，IR和AMPK之间的相互作用可能代表了一种新的调节脂质氧化和胰岛素敏感性，这是在肥胖肌肉破坏。作为我们揭示导致各种肥胖相关疾病的分子机制的长期目标的一部分，我们阐述了以下研究来描述IR/PIKE-A/AMPK相互作用在肥胖诱导的肌肉胰岛素抵抗和脂质氧化缺陷中的作用。本课题的主要内容是：（1）研究IR、PIKE-A和AMPK复合物的分子和功能，（2）研究IR/PIKE-A和PIKE-A/AMPK复合物形成的调控机制，特别是脂毒性和炎性细胞因子;和（3）研究肌肉特异性PIKE敲除小鼠中肥胖诱导的病理学，以证明IR/PIKE-A/AMPK在能量和葡萄糖稳态中的相互作用。综上所述，我们的研究将为解释肥胖组织中胰岛素信号和脂质代谢的改变提供一个新的机制，这是有帮助的 提高我们对肥胖病理生理学的理解，并改善其并发症的治疗设计。